Limited-duration anabolic therapy in postmenopausal osteoporosis

项目总结 三分之一的女性和五分之一的男性会在一生中经历骨质疏松性骨折。每个人 每年有超过30万65岁以上的人因髋部骨折而住院，这种骨折与一种 年死亡率为20-30%。目前的骨质疏松治疗降低了高危患者的椎体骨折风险 但它们降低非脊椎骨折和髋部骨折风险的能力尤其有限。最多的 最近批准的骨质疏松症药物romosozumab具有独特的作用机制，因为它既 刺激新骨形成，抑制骨吸收。然而，这些行动的时机不同， 它对新骨形成的刺激是暂时的，只持续1-3个月，而它对骨的抑制 再吸收是持续的。最近，romosozumab被证明可以降低脊柱和非脊柱疾病的风险。 骨折比骨质疏松症最广泛使用的药物阿仑磷酸钠更多。FDA最近批准了 然而，romosozumab伴随着一个“黑匣子”警告，因为研究报告了显著的 增加主要不良心脏事件的风险，包括中风、心肌梗死和心血管疾病 死亡。因为romosozumab只能短暂地刺激骨形成，我们假设一个更短的 Romosozumab疗程，然后是一种有效但选择性地抑制骨吸收的药物，将有 疗效与标准的12个月罗莫佐单抗疗程相似。这种较短疗程的romosozumab将 更具成本效益，更容易被患者接受(罗莫佐单抗每2次注射一次 月)，并可能降低罗莫佐单抗介导的主要不良心脏事件的风险。在这 提案，我们将通过一项为期12个月的开放标签原则证明临床试验来检验我们的假设 骨折风险较高的绝经后妇女将接受罗莫佐单抗治疗3个月，然后 用于9个月或标准12个月治疗的抗吸收药物Denosumab 罗莫佐珠单抗。这项研究的主要终点是双能X射线吸收测量法的变化 0-12个月的总髋部骨密度。其他部位骨密度的变化，生化 骨代谢标记物，高分辨率QCT衍生的间隔室体积骨密度， 小梁骨微结构，以及骨皮质结构，以及估计 通过有限元分析评估的骨强度将被评估为关键的次要或探索性终点。 拟议研究的成功完成将定义一种更安全、更便宜和更合理的 一种有前景的骨质疏松新药的使用方法。通过这样做，这项研究有可能 从根本上改变骨质疏松症的治疗方式，特别是对那些严重和 已确定的疾病。

PROJECT SUMMARY One in three women and one in five men will experience an osteoporotic fracture during their lifetime. Each year over 300,000 people over the age of 65 are hospitalized for hip fractures which are associated with a 1- year mortality rate of 20-30%. Current osteoporosis therapies reduce vertebral fracture risk in high-risk patients but their ability to reduce the risk of non-vertebral fractures and hip fractures, specifically, is modest. The most recently approved osteoporosis medication, romosozumab, has a unique mechanism of action in that it both stimulates new bone formation and inhibits bone resorption. The timing of these actions, however, differs in that its stimulation of new bone formation is transient, lasting only 1-3 months, whereas its inhibition of bone resorption is sustained. Recently, romosozumab was shown to reduce the risk of both spine and non-spine fractures more than the most widely used osteoporosis medication, alendronate. The recent FDA approval of romosozumab, however, was accompanied by a “black box” warning as studies reported a significant increased risk of major adverse cardiac events including stroke, myocardial infarction, and cardiovascular death. Because romosozumab only transiently stimulates bone formation, we hypothesize that a much shorter course of romosozumab, followed by a drug that potently but selectively inhibits bone resorption, would have similar efficacy to the standard 12-month course of romosozumab. This shorter course of romosozumab would be significantly more cost effective, more acceptable to patients (romosozumab is given as 2 injections every month) and would likely reduce the romosozumab-mediated risk of major adverse cardiac events. In this proposal, we will test our hypothesis via a single open-label proof-of-principle 12-month clinical trial in which postmenopausal women at a high risk of fracture will receive either romosozumab for 3 months followed by the antiresorptive medication, denosumab, for the 9 months or the standard 12-months treatment with romosozumab. The primary endpoint of the study is the changes in dual-energy X-ray absorptiometry-derived total hip bone mineral density from months 0-12. Changes in bone mineral density at other sites, biochemical markers of bone metabolism, high-resolution QCT-derived compartmental volumetric bone mineral density, trabecular bone microarchitecture, and cortical bone structure of the radius and tibia, as well as estimated bone strength assessed by finite element analysis will be assessed as key secondary or exploratory endpoints. The successful completion of the proposed study will define a safer, less expensive, and more rational approach to the use of a promising new osteoporosis medication. In so doing, this study has the potential to fundamentally change the way osteoporosis is treated, especially for those patients with severe and established disease.